Background: The COVID-19 pandemic has significantly affected mental health and overall quality of life, particularly in epicenter regions such as DKI Jakarta Province, Indonesia. This study aimed to analyze the association between mental health disorders and health-related quality of life (HRQoL) during the COVID-19 pandemic. Materials and Methods: A mixed-methods design was employed, combining a cross-sectional survey of 300 participants in East Jakarta conducted from July to November 2021 with qualitative approaches, including focus group discussions (FGDs), in-depth interviews, and observations. The Self-Reporting Questionnaire (SRQ) and the Indonesian version of the HRQoL instrument were used for data collection. Cox regression analysis was performed to assess the association between mental health disorders and quality of life. Results: The findings showed that 23.3% of respondents experienced mental health disorders, and 25.3% reported poor quality of life. A significant association was observed between mental health disorders and reduced quality of life after adjusting for literacy (Adjusted PR = 1.957; 95% CI: 1.243–3.082). The qualitative findings highlighted emotional distress, anxiety, fear of infection, social stigma, and financial difficulties as key contributing factors. Conclusion: This study demonstrates that mental health disorders played a crucial role in diminishing quality of life during the COVID-19 pandemic. Mitigation strategies, such as improving mental health literacy and strengthening social support systems, are essential to enhance public well-being. © 2026 African Traditional, Herbal Medicine Supporters Initiative. All rights reserved.